Mammalian bone tissue has a remarkable ability to regenerate and thereby repair injuries and other defects. Underlying the remodeling process are cells of the osteoblast lineage, which participate in bone formation, and cells of the osteoclast lineage, which participate in bone resorption. These two types of cells are known to originate from distinct early progenitor cells, i.e. stem cells, which differentiate along separate pathways into mature and functional cells, in response to such endogenous mediators as systemic hormones, cytokines and growth factors.
Bone growth is generally sufficient to bring about full recovery for most simple and hairline fractures. Unfortunately, however, there are many injuries, defects or conditions where bone growth is inadequate to achieve an acceptable outcome. For example, bone regeneration generally does not occur throughout large voids or spaces. Therefore, fractures cannot heal unless the pieces are in close proximity. If a significant amount of bone tissue is lost as a result of an injury, the healing process may be incomplete, resulting in undesirable cosmetic and/or mechanical outcomes. This is often the case with non-union fractures or with bone injuries resulting from massive trauma. Tissue growth is also generally inadequate in voids and segmental gaps in bone caused, for example, by surgical removal of tumors or cysts. In other instances, it may be desirable to stimulate bone growth where bone is not normally found, i.e., ectopically. Spine fusion to relieve lower back pain where two or more vertebrae are induced to fuse is one example of desirable ectopic bone formation.
Currently, such gaps or segmental defects require autogenous bone grafts for successful repair or gap filling. The development of effective bone graft substitutes would eliminate the need to harvest bone from a second surgical site for a graft procedure, thereby significantly reducing the discomfort experienced by the patient and risk of donor site healing complications.
Compounds, which stimulate or induce bone growth at sites where such growth would not normally occur if left untreated, are said to be “osteoinductive”. Many osteoinductive compounds have been isolated and biochemically identified, and recombinant DNA technologies have been applied to produce relatively large quantities of those having a protein-based structure. These compounds include acidic or basic fibroblast growth factors, platelet-derived growth factor, members of the transforming growth factor superfamily of proteins, insulin-like growth factor, bone morphogenic proteins, etc.
The potential utility of osteogenic proteins has been recognized widely. It is contemplated that the availability of the protein would revolutionize orthopedic medicine, certain types of plastic surgery, and various periodontal and craniofacial reconstructive procedures. However, the use of recombinant proteins as therapeutic agents generally has a number of drawbacks, including the cost of manufacture, in vivo biodegradation, short shelf lives and immunogenicity because of their large molecular weight. Consequently, scientists are continuing to search for new osteoinductive agents, which do not have the aforementioned shortcomings.
A variety of pathological disorders, as well as physical stress (for example, fracture) necessitate active formation of bone tissue at rates that are significantly higher than that which can be supported by the normal milieu of the body. Thus, there is a need in the art to identify physiologically acceptable agents which do not suffer from the disadvantages noted above and which can induce the formation of bone at a predetermined site. Such agents would desirably either provide a permissive matrix structure for the deposition of bone-forming cells or cause growth stimulation of bone-forming cells or induce the differentiation of appropriate progenitors of bone-forming cells.